The oxidation state of DJ-1 regulates its chaperone activity toward α-synuclein

Wenbo Zhou, Min Zhu, Mark A. Wilson, Gregory A. Petsko, Anthony L. Fink

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279 Scopus citations

Abstract

DJ-1 has been reported to have chaperone activity by preventing the aggregation of some proteins, and by structural analogy to Hsp31. The L166P mutation has been linked to a familial early onset form of Parkinson's disease (PD). Since the aggregation of α-synuclein is believed to be a critical step in the etiology of PD, we have investigated the interaction of wild-type DJ-1 and its oxidized forms with α-synuclein. Native (unoxidized) DJ-1 did not inhibit α-synuclein fibrillation, and no evidence for stable interactions between α-synuclein and native DJ-1 was observed. However, DJ-1 is very susceptible to oxidation by the addition of two oxygen atoms to form the sulfinic acid of Cys106 (2O DJ-1) (no 1O oxidized state is detectable). 2O DJ-1 was readily prepared by the addition of H2O2 at concentrations up to a 20-fold molar excess. The oxidation of Cys106 to the sulfinic acid had minimal effect on the structural properties of DJ-1. However, 2O DJ-1 was very effective in preventing the fibrillation of α-synuclein, and only this form of DJ-1 appears to have significant anti-aggregation properties against α-synuclein. Further oxidation of DJ-1 leads to loss of some secondary structure, and to loss of the ability to inhibit α-synuclein fibrillation. Our observations confirm the suggestion that DJ-1 may act as an oxidative-stress-induced chaperone to prevent α-synuclein fibrillation. Since oxidative stress has been associated with PD, this observation may explain why mutations of DJ-1 could be a contributing factor in PD, and also indicates that excess oxidative stress could also lead to enhanced α-synuclein aggregation and hence PD.

Original languageEnglish (US)
Pages (from-to)1036-1048
Number of pages13
JournalJournal of Molecular Biology
Volume356
Issue number4
DOIs
StatePublished - Mar 3 2006

Keywords

  • Aggregation
  • DJ-1
  • Fibrillation
  • Parkinson's disease
  • α-synuclein

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